Background-We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing. Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4. Methods and Results-Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer. Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34Ϯ23, 58Ϯ15 (Pϭ0.027), 74Ϯ10 (Pϭ0.002), and 89Ϯ7 (Pϭ0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55Ϯ12 versus 42Ϯ12% platelet aggregation; Pϭ0.002), as did troleandomycin (78Ϯ18 versus 45Ϯ18% platelet aggregation; PϽ0.0003), whereas rifampin enhanced platelet aggregation inhibition (33Ϯ18 versus 56Ϯ20% platelet aggregation, Pϭ0.001). Conclusions-CYP3A4 activates clopidogrel. Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation. Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel. (Circulation. 2003;107:32-37.)Key Words: drugs Ⅲ pharmacology Ⅲ platelets Ⅲ statins C lopidogrel inhibits platelet aggregation. 1 It decreases the incidence of coronary artery stent thrombosis and is approved for reduction of myocardial infarction, stroke, and vascular death in patients with atherosclerotic vascular disease. [2][3][4] Clopidogrel is an inactive thienopyridine prodrug that requires in vivo conversion in the liver to an active metabolite that exerts its antiplatelet effect by forming an inactivating disulfide bond with the platelet P2Yac (P2Y12) adenosine diphosphate (ADP) receptor. [5][6][7][8] The P2Yac ADP receptor is a guanosine triphosphate (GTP)-coupled 7 transmembrane protein that mediates platelet aggregation by inhibiting adenyl cyclase. 8 In rats, it has been suggested that clopidogrel is activated by cytochrome P450 1A2, 6 whereas an analogue of clopidogrel, CS-747, is speculated to be activated by human cytochrome P450 3A4 (CYP3A4). 9 In humans, it is not known how clopidogrel is activated.Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor widely used to treat hypercholesteremia. It is metabolized by CYP3A4, 10 the most abundant cytochrome P450 in human liver. Patients with atherosclerotic disease are frequently treated for hypercholesteremia with both clopidogrel and atorvastatin or another statin.During the course of evaluating the effect of clopidogrel on platelet function using a novel bedside platelet aggregometer, it was noted that the antiplatelet activity of clopidogrel...

The authors observed the incidence of grade 3 MV to be 1.4%, similar to studies with the same definition of difficult MV. Presence of a beard is the only easily modifiable independent risk factor for difficult MV. The mandibular protrusion test may be an essential element of the airway examination.

Children may become agitated after general anesthesia. This study describes several factors that may increase the risk for agitation. These data are important in planning anesthesia care for young children.

Background-Interindividual variability of platelet inhibition after aspirin or clopidogrel administration has been described. Additionally, aspirin resistance and clopidogrel resistance occur in some individuals. Because the prodrug clopidogrel is activated by hepatic cytochrome P450 (CYP) 3A4, we hypothesized that interindividual variability in clopidogrel efficacy might be related to interindividual differences in CYP3A4 metabolic activity. Methods and Results-Platelet aggregation was measured before and after clopidogrel treatment in 32 patients undergoing coronary artery stent implantation and in 35 healthy volunteers. The erythromycin breath test was used to measure CYP3A4 activity in vivo in 25 of the healthy volunteers. Individual platelet aggregation was studied in 10 healthy volunteers after the coadministration of clopidogrel and rifampin (a CYP3A4 inducer). Clopidogrel nonresponders, low responders, and responders were defined by a relative inhibition of adenosine diphosphate (20 mol/L)-induced platelet aggregation of Ͻ10%, 10% to 29%, and Ն30%, respectively. Among patients, 22% were clopidogrel nonresponders, 32% were low responders, and 47% were responders. Among volunteers, 16% were nonresponders, 12% were low responders, and 72% were responders. Percent platelet aggregation after clopidogrel inversely correlated with CYP3A4 activity (rϭϪ0.6, Pϭ0.003). Improved platelet inhibition in volunteers resistant to clopidogrel was observed with the coadministration of clopidogrel and rifampin. Conclusions-Clopidogrel administration results in interindividual variability in platelet inhibition, which correlates with CYP3A4 metabolic activity. Measurement of antiplatelet drug efficacy with a point-of-care device and alternative antithrombotic strategies for aspirin or clopidogrel nonresponders and low responders could reduce the incidence of thrombotic events that continue to occur despite oral antiplatelet therapy. Key Words: drugs Ⅲ platelets Ⅲ pharmacology C lopidogrel, a thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate (ADP). 1 Clopidogrel was approved by the United States Food and Drug Administration (FDA) in 1997 for the reduction of myocardial infarction, stroke, and vascular death in patients with recent stroke, recent myocardial infarction, or established peripheral arterial disease after the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial 2 showed superior reduction of these events with clopidogrel compared with aspirin (annual risk, 5.3% versus 5.8%; Pϭ0.04). Dual antiplatelet therapy (aspirin plus clopidogrel) for acute coronary syndromes was approved by the FDA in 2002 on the basis of the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial 3 results, which showed a significant reduction in the 9-month composite end point of cardiovascular death, nonfatal myocardial infarction, or stroke versus aspirin monotherapy (9.3% versus 11.4%, PϽ0.001). Additionally, the c...

Quality assurance data were collected prospectively for children who were sedated (n = 922) or given general anaesthesia (n = 140) for magnetic resonance imaging (MRI) or computerized tomography (CT). The data included patient characteristics, concurrent medication, adequacy of sedation, adverse events and requirement for escalated care. The quality of scans was evaluated. Reasons for preselection of general anaesthesia included previously failed sedation (28%), potential for failed sedation (32%) and perceived medical risk (14%). Hypoxaemia occurred in 2.9% of sedated children, and was more common in children classified as ASA III or IV. Sedation was inadequate for 16% of children and failed in 7%. Failed sedation was associated with greater age (P = 0.009), higher ASA status (P = 0.04) and use of benzodiazepines as sole sedatives (P < 0.03). More of the children who underwent general anaesthesia were ASA III or IV than sedated children, yet the procedure was successful in all the children who underwent general anaesthesia, with one incident of laryngospasm. Excessive motion was noted in 12% of scans of sedated children and 0.7% of those completed with general anaesthesia. We conclude that sedation of children for MRI and CT is associated with risks of hypoxaemia and of inadequate or failed sedation. These adverse events were more likely to occur in older children, those with a higher ASA status and those in whom benzodiazepines had been used as sole sedatives. For a preselected high-risk group of children, general anaesthesia may make MRI and CT scans more successful with minimal adverse events.

Findings support the reliability and validity of the FLACC as a measure of pain in children with CI.

The current study identified several risk factors for perioperative adverse respiratory events in children with lulls. Although children with acute and recent URIs are at greater risk for respiratory complications, these results suggest that most of these children can undergo elective procedures without significant increase in adverse anesthetic outcomes.

The UMSS is a simple, valid and reliable tool that facilitates rapid and frequent assessment and documentation of depth of sedation in children.